DNA recombination, DNA repair, and RNA splicing are multistep processes that rely on protein complexes (Coleman J E et al (1980) CRC Crit Rev Biochem 7: 247-289). These complexes may bind, unwind, anneal, cleave, and otherwise modify DNA or RNA. Typically, several protein subunits contribute to these complexes.
In a search for molecules that enable plants to resist the DNA damaging effects of ultraviolet radiation, researchers discovered the Arabidopsis thaliana Drt111 protein (Pang Q et al (1993) Nuc Acids Res 21: 1647-1653). Drt111 partially restores recombination proficiency and DNA-damage resistance to E. coli ruvC mutants, cleaving single-stranded DNA in homologous recombination intermediates (Holliday junctions).
Nucleic acid binding and modifying proteins are also required for splicing pre-mRNA in the cell nucleus. One such protein is the U2 snRNP auxiliary factor (U2AF) which has been shown to bind pre-mRNA (Zamore P et al (1992) Nature 355: 609-614). U2AF belongs to a family of splicing factor genes that possess multiple repeats of the RS dipeptide at either their N or C terminus. The RS domain has been shown to be essential for annealing complementary RNA or DNA sequences and for binding RNA (Lee C G et al (1993) J Biol Chem 268: 13472-13478).
Nucleic Acid Binding Proteins and Disease
One of the hallmarks of Alzheimer's disease is the deposition of a processed form of amyloid precursor protein (APP) outside of brain cells (Soto C et al (1994) J Neurochem 63: 1191-1198). As P19 EC cells differentiate into glial cells, expression of U2AF is reduced and APP is alternatively spliced Transfection with U2AF restores the original APP splice variant, thus U2AF is believed to play a critical role in glial-specific splicing of APP (Tsukahara T et al (1995) Brain Res 679: 178-183).
Auto-antibodies against snRNPs were found to be common in systemic lupus erythematosus (SLE) and related autoimmune disorders (Fisher D E et al (1984) Proc Natl Acad Sci 81: 3185-3189). Later, auto-antibodies to U2 snRNP and the other snRNPs were found to be diagnostic for SLE (Hermann H et al EMBO J 14: 2076-2088). In cell culture experiments, Koren et al (1995, J Immunol 154: 4857-4864) found that antibodies derived from a murine model for SLE were pathogenic only when they had reactivity with snRNP components. Thus, an autoimmune response to snRNP components appears to be important in SLE pathology.
More than a million Americans suffer from dementia, a permanent and often progressive decline in intellectual function that substantially interferes with a person's social and economic activity. Alzheimer's disease is a major cause of dementia and its prevalence is growing. Currently, there are no known treaments that stop or reverse the relentless progression in the impairment in mental abilities of Alzheimer's disease patients. Similarly, there are no known treatments that permanently end SLE. Current treatments for SLE control the inflammatory responses that are a consequence of SLE, but do not mask the antigen that promotes the production of self-reactive immune cells. Thus, a new nucleic acid binding protein would satisfy this need in the art by providing new agents for the diagnosis and treatment of Alzheimer's disease and various autoimmune disorders such as SLE.